IRF4 deficiency vulnerates B progeny for leukemogenesis via Jak3 mutations resembling Ph-like B-ALL in humans

How disturbances of B cell development provoke adult B acute lymphoblastic leukemia (B-ALL) remains poorly understood. Here we describe Irf4 KO mice as prone to developing B-ALL with age. Irf4 KO pro/preB cells exhibited impaired differentiative but enhanced proliferative potential in vitro and accumulated in spleens of healthy Irf4 KO mice, suggesting reduced adherence to the IL-7 providing bone marrow niche. Thus selected, pro/preB cells transformed acquiring proliferative IL-7 independency through Jak3 gain-of-function mutations. Targeting JAK signaling with Ruxolitinib in vivo prolonged survival of mice bearing established Irf4 KO leukemia. Intriguingly, organ infiltration including leukemic meningeosis was selectively reduced without affecting blood blast counts. As low IRF4 expression and JAK3 mutations also characterize a subpopulation of Ph-like B-ALL in adult humans, our results imply Irf4 KO mice as a suitable model for investigating preleukemic conditions in adults. Using this model, we identified an unexpected effect of Ruxolitinib treatment in B-ALL.